Comprehensive Mutational and Phenotypic Characterization of New Metastatic Cutaneous Squamous Cell Carcinoma Cell Lines Reveal Novel Drug Susceptibilities

Perry, Jay; Ashford, Bruce; Thind, Amarinder Singh; Gauthier, Marie-Emilie; Minaei, Elahe; Major, Gretel; Iyer, N. Gopalakrishna; Gupta, Ruta; Clark, Jonathan; Ranson, Marie

doi:10.3390/ijms21249536

Cited by 11 publications

(37 citation statements)

References 61 publications

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“…In general, the present study found that tumor-, subtype- and patient-specific features were conserved in the cell lines compared to their original tissue samples, while genes associated with immune response, cell adhesion and angiogenesis were downregulated. This is consistent with the results by Perry et al, who compared two human squamous cell carcinoma cell lines to their original tumor tissues [ 42 ]. Importantly, regarding the tumor entity, only few deviations were found between cell lines and tissues regarding the prostate and bladder cancer pathways.…”

Section: Discussionsupporting

confidence: 93%

“…The optimal reference for characterizing a cell line is the original tissue from which it was initially derived. However, in most cases, such a sample is either not available or not suitable for RNA-seq, and thus, such studies are scarce [ 42 ]. The sample set analyzed herein, consisting of canine cell lines derived from four PAC, two PAC metastases and three TCC and their original tumor tissues, provides a rare opportunity.…”

Section: Discussionmentioning

confidence: 99%

“…It provides an overview of the complete gene expression landscape and enables detailed single gene expression analyses of therapeutically relevant targets [ 10 , 21 , 40 , 41 ]. Specifically, the comparative characterization of the transcriptome of cell lines and their original tumor tissues as performed here has been proved a powerful approach to identify similarities and discrepancies between them [ 42 ]. Alas, for many established cell lines, the original tumor tissue is not available or its quality is unsuitable for RNA sequencing and therefore, transcriptome level comparisons are rare [ 42 ].…”

Section: Introductionmentioning

confidence: 99%

“…Specifically, the comparative characterization of the transcriptome of cell lines and their original tumor tissues as performed here has been proved a powerful approach to identify similarities and discrepancies between them [ 42 ]. Alas, for many established cell lines, the original tumor tissue is not available or its quality is unsuitable for RNA sequencing and therefore, transcriptome level comparisons are rare [ 42 ]. Comparing cell lines to the original tumor tissue in a whole-transcriptome sequencing approach, this study revealed conserved patient-specific characteristics, EMT-properties and downstream PI3K-AKT signaling, along with unique therapeutic target signatures and cell-culture-related adaptations.…”

Section: Introductionmentioning

confidence: 99%

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RNA-seq of nine canine prostate cancer cell lines reveals diverse therapeutic target signatures

et al. 2022

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Background Canine prostate adenocarcinoma (PAC) and transitional cell carcinoma (TCC) are typically characterized by metastasis and chemoresistance. Cell lines are important model systems for developing new therapeutic strategies. However, as they adapt to culturing conditions and undergo clonal selection, they can diverge from the tissue from which they were originally derived. Therefore, a comprehensive characterization of cell lines and their original tissues is paramount. Methods This study compared the transcriptomes of nine canine cell lines derived from PAC, PAC metastasis and TCC to their respective original primary tumor or metastasis tissues. Special interests were laid on cell culture-related differences, epithelial to mesenchymal transition (EMT), the prostate and bladder cancer pathways, therapeutic targets in the PI3K-AKT signaling pathway and genes correlated with chemoresistance towards doxorubicin and carboplatin. Results Independent analyses for PAC, PAC metastasis and TCC revealed 1743, 3941 and 463 genes, respectively, differentially expressed in the cell lines relative to their original tissues (DEGs). While genes associated with tumor microenvironment were mostly downregulated in the cell lines, patient-specific EMT features were conserved. Furthermore, examination of the prostate and bladder cancer pathways revealed extensive concordance between cell lines and tissues. Interestingly, all cell lines preserved downstream PI3K-AKT signaling, but each featured a unique therapeutic target signature. Additionally, resistance towards doxorubicin was associated with G2/M cell cycle transition and cell membrane biosynthesis, while carboplatin resistance correlated with histone, m- and tRNA processing. Conclusion Comparative whole-transcriptome profiling of cell lines and their original tissues identifies models with conserved therapeutic target expression. Moreover, it is useful for selecting suitable negative controls, i.e., cell lines lacking therapeutic target expression, increasing the transfer efficiency from in vitro to primary neoplasias for new therapeutic protocols. In summary, the dataset presented here constitutes a rich resource for canine prostate and bladder cancer research.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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RNA-seq of nine canine prostate cancer cell lines reveals diverse therapeutic target signatures

et al. 2022

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“…Many commercial drug libraries are available to screen for targeted inhibitors that may impact survival of cell lines in vitro . Multiple array-based drug screens have been performed in HNSCC cell lines and primary HNSCC cells in 2D tissue culture, to identify synergistic drug combinations or new targets for therapy [ 139 , 140 , 141 , 142 , 143 , 144 ]. These screens prominently identified many cell cycle and DNA damage response inhibitors impacting survival of HNSCC cells.…”

Section: Identification Of Essential Genes In (Pre)hnscc Cells By Descriptive and Functional Genomicsmentioning

confidence: 99%

Targeted Treatment of Head and Neck (Pre)Cancer: Preclinical Target Identification and Development of Novel Therapeutic Applications

Harten

Brakenhoff

2021

Cancers

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Head and neck squamous cell carcinomas (HNSCC) develop in the mucosal lining of the upper-aerodigestive tract. In carcinogen-induced HNSCC, tumors emerge from premalignant mucosal changes characterized by tumor-associated genetic alterations, also coined as ‘fields’ that are occasionally visible as leukoplakia or erythroplakia lesions but are mostly invisible. Consequently, HNSCC is generally diagnosed de novo at more advanced stages in about 70% of new diagnosis. Despite intense multimodality treatment protocols, the overall 5-years survival rate is 50–60% for patients with advanced stage of disease and seems to have reached a plateau. Of notable concern is the lack of further improvement in prognosis despite advances in treatment. This can be attributed to the late clinical presentation, failure of advanced HNSCC to respond to treatment, the deficit of effective targeted therapies to eradicate tumors and precancerous changes, and the lack of suitable markers for screening and personalized therapy. The molecular landscape of head and neck cancer has been elucidated in great detail, but the absence of oncogenic mutations hampers the identification of druggable targets for therapy to improve outcome of HNSCC. Currently, functional genomic approaches are being explored to identify potential therapeutic targets. Identification and validation of essential genes for both HNSCC and oral premalignancies, accompanied with biomarkers for therapy response, are being investigated. Attentive diagnosis and targeted therapy of the preceding oral premalignant (preHNSCC) changes may prevent the development of tumors. As classic oncogene addiction through activating mutations is not a realistic concept for treatment of HNSCC, synthetic lethality and collateral lethality need to be exploited, next to immune therapies. In recent studies it was shown that cell cycle regulation and DNA damage response pathways become significantly altered in HNSCC causing replication stress, which is an avenue that deserves further exploitation as an HNSCC vulnerability for treatment. The focus of this review is to summarize the current literature on the preclinical identification of potential druggable targets for therapy of (pre)HNSCC, emerging from the variety of gene knockdown and knockout strategies, and the testing of targeted inhibitors. We will conclude with a future perspective on targeted therapy of HNSCC and premalignant changes.

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Protocol for the generation and automated confocal imaging of whole multi-cellular tumor spheroids

et al. 2023

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Comprehensive Mutational and Phenotypic Characterization of New Metastatic Cutaneous Squamous Cell Carcinoma Cell Lines Reveal Novel Drug Susceptibilities

Cited by 11 publications

References 61 publications

RNA-seq of nine canine prostate cancer cell lines reveals diverse therapeutic target signatures

RNA-seq of nine canine prostate cancer cell lines reveals diverse therapeutic target signatures

Targeted Treatment of Head and Neck (Pre)Cancer: Preclinical Target Identification and Development of Novel Therapeutic Applications

Protocol for the generation and automated confocal imaging of whole multi-cellular tumor spheroids

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